PREDICTION OF THE THERAPEUTIC EFFECTIVENESS OF NEW DRUGS FROM CLINICAL PHARMACOLOGY STUDIES

The development of new drugs for therapeutic purposes has become very expensive and time-consuming in American and European countries.It is estimated that on the average 50 to 100 million dollars and 10 or more years from the time of patenting are required to make a new drug available for general prescription. Every new drug needs to be charac-

Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury

Traumatic spinal cord injury is a devastating disorder chara cterized by sensory,motor,and autonomic dysfunction that seve rely compromises an individual's ability to perform activities of daily living.These adve rse outcomes are closely related to the complex mechanism of spinal cord injury,the limited regenerative capacity of central neurons,and the inhibitory environment fo rmed by traumatic injury.Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury.A number of therapeutic agents have been shown to improve the injury environment,mitigate secondary damage,and/or promote regeneration and repair.Among them,the spinal cord microcirculation has become an important target for the treatment of spinal cord injury.Drug inte rventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury.These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neuro ns,axons,and glial cells.This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury,including its structure and histopathological changes.Further,it summarizes the progress of drug therapies targeting the spinal cord mic rocirc ulation after spinal cord injury.

The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration: new pharmacological concepts for old and new drugs

Neurotrophins：Neurotrophins are peptides or proteins that are known to regulate neuronal viability,development,and function Beyond synaptic plasticity,neurotrophins protect neurons from apoptosis and also promote neurogenesis to recover neuronal defici even in adulthood.

Study on medication rules of Chinese herbs in the regulation of necroptosis based on network pharmacology and data mining

Objective:To analyze the basis and medication rules of Chinese herbs in the regulation of necroptosis.Methods:With the help of GeneCards,DrugBank,TTD,DisGeNET,OMIM database to collect the action targets of necroptosis,the TCMSP database to obtain the target‑related compounds and Chinese herbs,and the ADME criteria and Lipinski rule as the conditions for screening,to build the target‑compound,target‑compound‑Chinese herbs network.The information of Chinese herbal medicine's sexual taste and meridian was collected,and the drug use pattern was analyzed.The information on the property,flavor and channel tropism of Chinese herbs was collected to analyze the medication laws.Molecular docking of core targets and compounds in the network with AutoDockTools software,and PyMOL software was used to display the combinations with good docking results.Results:A total of 12 potential targets acting on necroptosis were obtained,matching to 191 candidate compounds and 366 herbal medicines.Quercetin,wogonin,triptolide,licochalcone a,ellipticine are more important and may be the main small molecule substances underlying the regulation of necroptosis.The more important Chinese herbs are Licorice,Forsythia,Salivae Miltiorrhizae,Ginkgo Leaf,Eucommia ulmoides Oliv,etc.The herbal medicines are mainly bitter and pungent,with cold and warm taste,which were attributed to the liver and lung meridians.BCL2‑beta‑sitosterol、MAPK14‑luteolin、MAPK14‑formononetin、TP53‑formononetin are better molecular docking results,which have strong docking activity.Conclusion:The study systematically analyzes the material basis of regulating necroptosis and summarizes the general rule of regulating necroptosis in Chinese medicine,which provides ideas for clinical development of agents to interfere with necroptosis.

Pharmacology and drug discovery

There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.

Did pediatric drug development advance epilepsy treatment in young patients?It is time for new research goals

Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.

Opinion on pharmacology research and new drug development from precision medicine

Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.

A review on the Pharmacology and Adverse Drug Reaction of Chaihu Herbal Injection

The Chaihu herbal injection was the first herbal injection to be developed and used in China,which has been used in clinic for more than 70 years.This injection is widely used to treat fever caused by influenza or common cold and malaria.However,there is an ongoing debate about the safety of the clinical use of Chaihu herbal injection in view of the large number of adverse drug reaction reports and literature in China.On May 29,2018,the China Food and Drug Administration issued a notice requiring to revise the instruction manual of Chaihu herbal injection,list"prohibit for children"under the taboo item,and add the warning"adverse reactions of this product include anaphylactic shock".The purpose of this review is to provide updated,comprehensive information on the pharmacology and adverse drug reaction of Chaihu herbal injection based on scientific literatures in the past few decades.

Energy pharmacological effects of chemical drugs

Background:To study the energy pharmacological effects of chemical drugs.Methods:The energy pharmacological effects of chemical drugs were studied using a literature induction method.Results:Chemical drugs have energy properties,which can be expressed in terms of cold,hot,warm,and cool.The energy properties of chemical drugs have energy pharmacological effects,which are related to the bond energy release and absorption of intermolecular chemical bonds,where the release of energy from chemical bonds indicates a warm-hot energy pharmacological effect and the absorption of energy indicates a cold energy pharmacological effect.The mechanisms of chemical drug energy may be related to the presence of temperature-sensitive ion channels in the body.Conclusion:Chemical drugs exhibit energy pharmacological effects.

Network pharmacology study of drug pair Tubeimu-Zhebeimu in the treatment of breast cancer

Objective:Breast cancer is a malignant tumor endangering women’s safety and health.Clinical medication experience and related studies show that the drug pairs Tubeimu-Zhebeimu has an excellent therapeutic effect on patients with breast cancer,but its treatment mechanism is unclear.In this study,network pharmacology and molecular docking were used to analyze and explore the mechanism of“Tubeimu-Zhebeimu”in treating breast cancer.Methods:Traditional Chinese Medicine Database and Analysis Platform were used to retrieve the chemical constituents of Tubeimu and Zhebeimu,and the relevant targets were predicted through the Swiss Target Prediction Database.Searching the Gene cards,Therapeutic Target Database and Disgenet Database with the keywords“breast cancer”,“mammary cancer”and“mammary adenocarcinoma”obtain disease-related targets.We intersect the disease target with the drug target to obtain the potential drug therapy target.Then the data was imported into Cytoscape 3.9.1 software to construct a compound network of“Disease-Target-Component-Drug”,and the network.Subsequently,using the String Database a“protein-protein interaction network”was constructed and imported into Cytoscape 3.9.1 software for structural optimization and network topology analysis.DAVID was used for Gene Ontolog function enrichment and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analyses,and the results were visualized.The core targets were molecularly docked through AutoDockTools-1.5.6 software and Auto Dock Vina 1.1.2 software.Results:The results showed that the 20 active ingredients in the“Tubeimu-Zhebeimu”includingβ-sitosterol,Chaksine,saponins,and peimuocinine,can treat breast cancer through 139 potential targets including AKT1,AR,TP53,ESR1.Conclusion:The specific mechanism of the drug pairs Tubeimu-Zhebeimu treating breast cancer may be controlling human hormone levels,inducing cell apoptosis,and participating in the P53 protein signaling pathway and PI3K/Akt/mTOR signaling pathway.

Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure

Although there have been significant advances in the treatment of heart failure in recent years,chronic heart failure remains a leading cause of cardiovascular disease-related death.Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure.However,most of the drugs that increase cardiac energy are still in the theoretical or testing stage.Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism.In this review,we summarized the mechanisms by which botanical drugs(the active ingredients/formulas/Chinese patent medicines)improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase(AMPK),peroxisome proliferator-activated receptors(PPARs)and other related targets.At the same time,some potential protective effects of botanical drugs on myocardium,such as alleviating oxidative stress and dysbiosis signaling,caused by metabolic disorders,were briefly discussed.

Recent advances in network pharmacology applications in Chinese herbal medicine

Network pharmacology is a new discipline based on the theory of systems biology and network analysis of biological systems to design the drugs.It comprehensively observes the intervention and influence of drugs on the disease network,and reveals the mystery of multi-molecular drugs synergistically acting on disease.These concepts reflect the ideas of multi-component,multi-target and system regulation,and have many similarities with the research ideas of traditional Chinese medicine,which focuses on syndrome differentiation and treatment,emphasizes the overall understanding of the etiology and pathogenesis.Network pharmacology can be used to predict and identify the target and active component of traditional herbal medicine,to clarify the mechanism of action,to scientifically explain the rules of the prescription,to explore the rules of real-world prescription,to discover new indications and new active compounds,and to study drug relocation,etc.The applications of network pharmacology in traditional herbal medicine were systematically summarized to demonstrate the significant value in these areas.

Pharmacology of tetrandrine and its therapeutic use in digestive diseases

INTRODUCTIONTetrandrine (Tet) is a dibenzylisoquinoline alkaloid isolatedfrom Stephania tetrandra S. Moore, a Chinese herbalmedicine. In the past decade, lots of studies demonstrated that Tet has multiple bioactivities, It is promising to use Tet as an antifibrogenetic in liver or lung fibrosis with or without portal or pulmonary hypertension, as well as an immunomodulating and anticarcinoma drug.

Study on the compatibility principle of Wutou Decoction based on network pharmacology

Objective To investigate the underlying drug enhancement mechanisms of the Chuanwu(Aconiti Radix)and Huangqi(Astragali Radix)combination and toxicity reduction of Chuan-wu combined with Gancao(Glycyrrhizae Radix et Rhizoma)in Wutou Decoction(乌头汤,WTD),and to elucidate the compatibility principle.Methods The active compounds and potential effective targets of the selected combinations were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and Traditional Chinese Medicines Integrated Database(TCMID).The toxicity of Chuanwu(Aconiti Radix)was investigated by selecting all five toxic compounds from the literature and the TCMSP database,and obtaining their targets through SwissTargetPrediction.Targets related to rheumatoid arthritis(RA)were searched using Dis-GeNET,GenCards,and Online Mendelian Inheritance in Man(OMIM).Mutual targets between the drug pairs and RA were selected as potential RA therapy targets.The medicinally active compound-target network was constructed using Cytoscape 3.9.0.Gene ontology(GO)term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrich-ment were performed using the Database for Annotation,Visualization,and Integrated Dis-covery(DAVID)platform.Results We obtained 191 active compound targets for Gancao(Glycyrrhizae Radix et Rhizoma),171 for Huangqi(Astragali Radix),and 103 for Chuanwu(Radix Aconiti)(hypo-aconitine’s target was obtained through literature and SwissTargetPrediction).A total of 5872 genes were obtained for RA.A drug-active compound-target network involving 13 effect-en-hancing and nine toxicity reduction targets was constructed.PGR was the main effect en-hancement target,and KCNH2 was the main toxicity reduction target.The effect-enhancing targets were related to 23 GO terms(such as positive regulation of transcription from RNA polymerase II promoter,steroid hormone-mediated signaling pathway,plasma membrane,and protein binding)(P<0.01),and 13 KEGG pathways related to synergism[such as estro-gen signaling pathway,cholinergic synapse,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt)signaling pathway].The toxicity reduction targets were related to 28 GO terms(mainly involes G-protein coupled receptor signaling pathway,plasma membrane,and drug binding)(P<0.01),and five KEGG pathways related to toxicity reduction(cholinergic syn-apse,calcium signaling pathway,regulation of actin cytoskeleton,neuroactive ligand-recept-or interaction,and serotonergic synapse).Conclusion The combination of Chuanwu(Aconiti Radix)and Huangqi(Astragali Radix)plays an important effect-enhancing role in WTD and involves the estrogen and PI3K/Akt sig-naling pathways,with PGR as the core.The Chuanwu(Aconiti Radix)and Gancao(Gly-cyrrhizae Radix et Rhizoma)combination decreases toxicity in WTD and is associated with the cholinergic synapse and calcium signaling pathways,with KCNH2 as the core.

Brain organoids are new tool for drug screening of neurological diseases

At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systematic reports on brain organoids,as a new three-dimensional in vitro model,in terms of model stability,key phenotypic fingerprint,and drug screening schemes,and particula rly rega rding the development of screening strategies for massive numbers of traditional Chinese medicine monomers.This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases.The paper also highlights the prospects from model stability,induction criteria of brain organoids,and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.

<i>In Silico</i>Pharmacological Analysis of a Potent Anti-Hepatoma Compound of Mushroom Origin and Emerging Role as an Adjuvant Drug Lead

Mushrooms are well-known to possess a continuum of anticancer metabolites that are vital in the development of anticancer adjuvant drug leads based on natural products. Owing to the fact that conventional cancer therapeutic methods were failed to lessen mortality caused by cancer to the estimated level with occurrence of adverse side effects, anticancer agents isolated from natural mushroom sources unarguably make an experimental research area worth mass focus today. The current study was targeted on in vitro cytotoxicity and in silico predictive pharmacological analysis of a flavonoid compound isolated from Fulvifomes fastuosus mushroom. Targeted compound was isolated from the mushroom using different chromatographic methods and identified by NMR spectrometry and mass spectrometry. Cytotoxicity experiments were carried out using MTT assay and apoptotic cells were identified by ethidium bromide/acridine orange staining. The SwissADME tool, BOILED-Egg construction model and Swiss target protein prediction software have been used to perform in silico predictive pharmacological analysis. The isolated compound has been identified as 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione by spectrometric methods. The result of MTT assay showed that 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has potent anticancer activity for hepatoma against Hep-G2 cell line (IC50 = 20.8 μg/ml) being less toxic to normal CC-1 epithelial cells (IC50 = 167.00 μM). The cells treated with compound ex-hibited apoptotic features such as cellular shrinkage, nuclear fragmentation and condensed cytoplasm. In summary, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has shown potent anticancer properties against hepatoma with less cytotoxicity effect on normal cells. Furthermore, in silico study has revealed that properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione may contribute to making a high absorption and clearance of the test compound as not interfering with the therapeutic failure of the compound. The properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo-[3,2-c]pyran-3,2'-furan]-3',4-dione were compatible with well-known anticancer drug lapatinib. In conclusion, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has a high tendency to act as a good anticancer adjuvant drug in the treatment of hepatoma.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Alzheimer′s disease using network pharma⁃cology approach and in vitro experimental validation

OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

Study on the mechanism of two related Chinese herbs Chenpi-Banxia in the treatment of coronary microvascular dysfunction based on network pharmacology

Objective:By the method of network pharmacology to study the main active compounds,main target genes,critical path and mechanism of the two classical Chinese herbs Chenpi-Banxia in the treatment of Coronary Microvascular Dysfunction(CMD).Methods:Obtaining potential active compounds of Chenpi-Banxia from TCMSP,while the targets for CMD were obtained from DrugBank and OMIM databases.Using UniProt database to query the corresponding gene name.The key target of Chenpi-Banxia in the treatment of Coronary Microvascular Dysfunction can be obtained by using the intersection of VENNY.The PPI network was screened for the major targets by String and Cytoscape3.7.1.The GO enrichment analysis and KEGG Pathway analyses of major targets were performed by using the DAVID database and use Binformatics to draw bubble map.Finally,the ingredient-major arget-key pathway network was constructed by Cytoscape3.7.1.Results:There were 16 compounds such as naringenin,nobiletin,baicalein.beta-sitosterol etc,and 56 predictive target genes such as AKT1、VEGFA、BCL2、BAX、JUN etc,as well as 20 key pathways including inflammation-related pathway(TNF signaling pathway),pathways related to cardiovascular system(PI3K-Akt signaling pathway),Vascular endothelial growth factor signaling pathway(VEGF signaling pathway),Apoptosis related pathways(Apoptosis)and Hypoxia cell stress signaling pathway(HIF-1 signaling pathway)in the Compounds-Target-Pathway network.Conclusion:The study verified the characteristics of multi-components,multi-targets and integral regulation for Chenpi-Banxia with the application of network pharmacology.It predicted that Chenpi-Banxia couldtreat Coronary Microvascular Dysfunction mainly by protecting endothelial cell function of coronary microcirculation,inhibiting cell apoptosis and affecting inflammatory reaction.

Research progress on pharmacological action and effective drug carrier of berberine

Berberine(BBR)is an isoquinoline alkaloid that can be extracted from the traditional Chinese medicine Huang Lian.It has anti-inflammatory,anti-cancer,protection of nerves,hypoglycemic,blood lipid,anti-oxidation,antibacterial and other effects.It can be used clinically to treat chronic colitis,bacterial vaginitis,rheumatoid arthritis,breast cancer,liver cancer,Alzheimer's disease,diabetes,obesity and other common diseases.This paper reviews the pharmacological effects of berberine and the research progress of effective drug carriers in order to provide new ideas for the clinical application of berberine.

Network pharmacology-based elucidation of molecular biological mechanisms of Qizhu Yuling Decoction for treatment of esophagus cancer

Objective:To investigate the active compounds,key targets and molecular mechanism of Qizhu Yuling Decoction in the treatment of esophageal carcinoma based on network pharmacology.Methods:The active compounds of Qizhu Yuling Decoction with anti-esophageal cancer activity were screened by TCMSP and literature search,and the drug targets were searched by DrugBank and predicted by SwissTargetPrediction.The esophageal cancer-related genes were obtained from GeneCards,OMIM,DrugBank,TTD,DisGeNET,and the intersection network was selected to obtain candidate genes.The"herb-compound-target-disease"network was constructed with Cytoscape,the PPI network was constructed in STRING and core network modules were screened.Gene ontology and KEGG enrichment analysis was performed by using Metascape,and the"pathway-gene"network was constructed to further screen key targets.Results:A total of 47 active compounds(19 Astragalus,4 Zedoary turmeric,11 Atractylodes macrocephala,9 Curcuma longa,5 Clematis root,and 5 Salvia chinensis),297 candidate genes,2413 GO and 119 KEGG pathways were obtained.Conclusion:The active compounds of Qizhu Yuling Decoction in the treatment of esophageal cancer are quercetin,kaempferol,glycine and ursolic acid.The potential targets are AKT1,MAPK1,MAPK3,PIK3R1 and RELA.GO involves oxidative stress,cell cycle,apoptosis and cell death,and KEGG involves typical cancer pathways,MAPK,NF-κB and PI3K-Akt signaling pathways.This study reveals the molecular biological mechanism of Qizhu Yuling Decoction in the treatment of esophageal cancer,and speculates that the function of potential targets focuses on the interaction of multiple signaling pathways,which can antagonize the proliferation,invasion,metastasis and recurrence of esophageal cancer and improve the prognosis of patients.This study provides new evidence for subsequent new drug development,clinical application and experimental study.